COMT inhibition and safety.

P a r k i n s o n ’s disease (PD) still has to be treated with dopaminergic drugs and levodopa is the most effective drug in the treatment of PD. Howe v e r, levodopa therapy presents two basic problems: its poor central availability (only about 1% of an oral levodopa dose reaches the brain) and its short elimination half-life (about one hour). Combination with a dopa-decarboxylase inhibitor (DDCI), which is the formulation currently used, significantly reduces the peripheral metabolism but, when the association is assumed, it is not able to prevent the metabolic switch by cathecol-o-methyltransferase (COMT). COMT rapidly converts levodopa into 3-0-methyldopa (3-OMD), which competes with levodopa for entry into the brain. Consequently, still only 5-10% of the administered levodopa dose reaches the striatum (1). COMT is abundant in the periphery, especially in the liver, kidney and gastrointestinal mucosa and is present in smaller amounts in the CNS; blocking this metabolic pathway of levodopa induces an increase in its elimination halflife while at the same time keeping plasma levodopa levels constant and not affecting the peak plasma levodopa levels or the time to reach the peak. This is the rationale behind the use of COMT inhibitors in PD and the advantages as regards motor function are based, in particular, on extending the length of “on” time, on improving wearing off phenomenon and on reducing “ o ff” time (2). Recent reports have cited continuous d o p a m i n e rgic stimulation as an important current concept in the therapy of PD, which could guar-